Methods of preparing cytotoxic benzodiazepine derivatives

Abstract

The invention relates to novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.

1 - 25 . (canceled) 
     
     
         26 . A method of preparing a compound of formula (12A): 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a compound of formula (1A), 
       
       
         
           
           
               
               
           
         
         with a halogenating reagent, a sulfonating reagent or an esterification reagent, 
         wherein:
 X 1  is —Br, —I, —Cl, a sulfonate ester or an activated ester. 
 
       
     
     
         27 . The method of  claim 26 , wherein X 1  is —Br or —I. 
     
     
         28 . The method of  claim 26 , wherein the halogenating reagent reacts with the primary alcohols of the compound of formula (1A) in the presence of an alcohol activating agent and wherein the alcohol activating agent is thionyl chloride and the halogenating reagent is lithium bromide, sodium bromide, potassium bromide, potassium iodide, or sodium iodide. 
     
     
         29 . A method of preparing a compound of formula (10A′), 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a compound of formula (12A), 
       
       
         
           
           
               
               
           
         
         with a monomer compound of the formula (b1), 
       
       
         
           
           
               
               
           
         
         wherein:
 X 1  is —Br, —I, —Cl, a sulfonate ester; or an activated ester (preferably, X 1  is —Br, —I, or a sulfonate ester). 
 
       
     
     
         30 . The method of  claim 29 , wherein the compound of formula (12A) is reacted with the monomer compound of formula (b1) in the presence of a base. 
     
     
         31 . The method of  claim 30 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. 
     
     
         32 . A method of preparing a compound of formula (7A′), 
       
         
           
           
               
               
           
         
         or a salt thereof, said method comprising reacting a compound of formula (10A′), 
       
       
         
           
           
               
               
           
         
         or a salt thereof, with an imine reducing agent,
 wherein: 
 X 1  is —Br, —I, —Cl, a sulfonate ester, or an activated ester. 
 
       
     
     
         33 . The method of  claim 32 , wherein the imine reducing reagent is sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al). 
     
     
         34 . The method of  claim 29 , wherein X 1  is mesylate. 
     
     
         35 . The method of  claim 29 , further comprising the steps of: (3) reacting the compound of formula (10A′) with a monomer compound of formula (d 1 ), 
       
         
           
           
               
               
           
         
         to form a compound of formula (18A), 
       
       
         
           
           
               
               
           
         
         (4) when P 3  is an amine protecting group, reacting the compound of formula (18A) with an amine deprotecting reagent to form a compound of formula (IA) 
       
       
         
           
           
               
               
           
         
       
       wherein:
 P 3  is H or an amine protecting group. 
 
     
     
         36 . The method of  claim 35 , wherein P 3  is H and the compound of (10A′) is reacted with the monomer compound of (d 1 ) to form a compound of (IA). 
     
     
         37 . The method of  claim 29 , further comprising the steps of: (3) reacting the compound (10A′) with an imine reducing reagent to form a compound (7A′), 
       
         
           
           
               
               
           
         
         (4) reacting the compound of formula (7A′) with a monomer compound of the formula (a1), 
       
       
         
           
           
               
               
           
         
         to form a compound of formula IA 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The method of  claim 37 , wherein X 1  is mesylate. 
     
     
         39 . The method of  claim 26 , further comprising the steps of: (2) reacting the compound of formula (12A) with a monomer compound of the formula (d 1 ), 
       
         
           
           
               
               
           
         
         to form a compound of a formula (7A-1), 
       
       
         
           
           
               
               
           
         
         (3) reacting the compound of formula (7A-1) with a monomer compound of the formula (b1), 
       
       
         
           
           
               
               
           
         
         to form a compound of formula (18A), 
       
       
         
           
           
               
               
           
         
         (4) when P 3  is an amine protecting group, reacting the compound of formula (18A) with an amine deprotecting reagent to form the compound of formula (IA). 
       
     
     
         40 . The method of  claim 39 , wherein P 3  is H and the compound of (10A′) is reacted with the monomer compound of (b1) to form a compound of (IA). 
     
     
         41 . The method of  claim 39 , wherein P 3  is P 2 ; the monomer compound is represented by formula (c 1 ): 
       
         
           
           
               
               
           
         
         and the compound of formula (18A) is represented by formula (11A), 
       
       
         
           
           
               
               
           
         
         wherein P 2  is an amine protecting group. 
       
     
     
         42 . The method of  claim 39 , wherein X 1  is mesylate.